People with diabetes experience severe, accelerated atherosclerosis, which leads to heart attack and stroke. Blood sugar control delays diabetic vascular complications, suggesting that blood sugar is a primary risk factor for diabetic cardiovascular disease. However, even in people with diabetes, atherosclerotic plaques still develop in regions where arteries divide or bend. This suggests that blood flow changes at these locations combine with low or high blood sugar to cause diabetic atherosclerosis. Endothelial cells line all blood contacting surfaces in the body. Healthy endothelial cells prevent atherosclerotic plaque formation by controlling blood vessel permeability and inflammation. In both disturbed flow and altered glucose, endothelial cells are dysfunctional and promote atherosclerotic plaque development. While these two conditions have been studied individually, the mechanism by which altered glucose increases atherosclerotic plaque development in disturbed blood flow regions has not yet been studied. Our research goal is to investigate how altered blood sugar and blood flow mechanics interact to cause accelerated atherosclerosis in diabetes. We previously showed that low and high glucose conditions change the way that endothelial cells respond to normal blood flow. In this proposal, our objective is to study low and high glucose effects on endothelial cells in normal or disturbed blood flow. We hypothesize that normal blood flow protects endothelial cells from glucose-induced damage, but that acute glucose changes exacerbate disturbed flow effects. We will involve graduate and undergraduate students in the research through co-operative education opportunities. Successful project completion will clarify how normal blood flow protects endothelial cells and disturbed flow accentuates cell damage. This will improve our understanding of how diabetic atherosclerosis remains a focal disease despite systemic glucose changes. In the future, this will create new therapies for diabetic vascular disease. The will also enhance research opportunities for undergraduate mechanical and biomedical engineering students by providing 6 month co-operative education positions in our cellular mechanotransduction laboratory. These experiences will expand student awareness of biomechanics research diversity while inspiring them to explore health research careers.